7-hydroxy coumarin derivative



March 29, 1966 H. RITTER ETAL. 3,243,441

7HYDROXY COUMARIN DERIVATIVE original Filed July 2e. 1962 au: BY Rou- -Emnmo Nn'z FRANCAS M. CRAWFORD United States Patent 1 claim. (ci. 26o-343.2)

This yapplication 4is a division of parent application Serial No. 212,657, tiled July 26, 196-2.

The administration of coronary vasodilators `is to bring about an enhanced blood low in the coronary vessels. The conventional coronary vasodilators, however, involve the disadvantage of exercising merely a non-speciiic vasodilator action on the coronary vessels because they simultaneously cause a dilatation `of other large blood vessel areas, which is symptomatic of a considerable decrease in blood pressure. This hypotension does not allow the use of the known coronary vasodilat-ors in hypotonic patients and in those having an lacute myocardial infarction. In suc-h cases the known agents may even evoke a paradoxical eiect -on the coronary vessels, namely a coronary lblood ow decreasing effe-ct (see Scheler and Bretschneider, Verhandlungen der deutschen Gesellschaft fr KreiSlaufforschun-g, vol. 26, page 254 (1960)). Moreover, the known coronary vasodilators have only a relatively short-term action.

Consequently, the objective of our interest has been directed to the development of such coronary vasodi-lato-rs as specifically dilate the coronary vessels `only and, thus, do not exhibit a hypotensive action and which especially possess a long-term activity.

Now, we have found that the desired properties inhere in the derivatives of the 7-hydroxy-coumarins of the general formula 7 2 RaO-M/:O wherein R1 is a substituent `of the group consisting of a hydrogen atom, an alkyl, alkenyl, aryl, aralkyl, heteroalkyl, laminoalkyland a carbalkoxyalkyl radical, R2 is a substituent of the group consisting of an alkyland aryl residue, R3 is a substituent of the group consisting of an alkenyl, carbalkoxyalkyl, carboxyalkyl, ca-rbamidoalkyl radical and, if R1 is an aminoalkyl radical, furthermore an alkyl radical and R4 is a substituent of the group consisting of a hydrogen atom and the residue -OR3.

The new 7hydroxycoumarin derivatives are obtained in the known methods by allowing 7-hydroxy-coumarins of the general formula wherein R4 is `a hydrogen `atom or a hydroxyl group, to react with halogen com-pounds of the formula R3hal, in the presence of an acid-binding agent, or by condensing with cyclization substituted hydroxy-cinnamic acids of the general formula or their lfunctional derivatives or by condensing oxybenzenes of the general formula RSO- OH with IB-keto-acid esters of the general formula or, if R3 has the meaning of a carbamido-alkyl radical, by aminating 7hydroxycoumarin derivatives of the general formula with ammonia or primary or secondary amines.

The 7-hydroxy-coumarins being required, inter alia, as starting products may be obtained according to known methods, by condensing in the presence of an acid condensation agent -keto-acid esters of the general formula being correspondingly substituted with hydroxybenzenes of the general formula HO- OH Following the pharmacological tests in laboratories, which are described hereinafter the most active derivatives of the 7-hydrox-y-coumarins has been subjected to clinical experimentation, the results of which will als-o be stated hereinafter.

The pharmacological investigation of the substances according to -our present invention with respect to their coronary vasodilator action was carried out in dogs according to the method disclosed by Eckenhoif. Hafkenschiel and Landmesser (Am. J. Physiol. 148, 582 (1947)).

The test preparations were applied intravenously to the animals narcotized. The coronary blood ow was measured by means of an automatic bubble ilow meter and the blood pressure was measured in the femoral artery by means of an Anderson glass-capsule manometer. Duing the test period the animals were given articial respiration. On these test conditions the dilation of the coronary artery being caused by the test :substance gives rise to a more rapid bubble flow, whereas a constriction of the corona-ry vessels becomes evident from a retardation of the bubble flow, which is recorded by a kyrnograph. In all these tests there was used papaverine as a comparative standard substance.

FIGURES 1 and 2 illustrate graphically the results obtained when using different amounts of papaverine in comparison to 3--diethylaminoethyl4methyl-coumarin- 7-ethyl oxyacetate chlorhydrate.

Within each figure:

Curve I represents the action of 0.4 nig/kg. papaverine,

Curve II represents the action of 0.8 mgJkg. papaverine,

Curve III represents the action of 0.8 mg./kg. S-,B-diethylaminoethyl-4-methy1 coumarin-7-ethyl oxyacetate chlorhydrate,

Curve IV represents the action of 1.265 mg./kg. 3di ethylaminoethyl-lt-methyl coumarin-7-ethyl oxyacetate chlorhydrate,

Curve V represents the action of 0.4 mg./kg. S--diethylaminoethyl-Lt-methyl coumarin-7-ethyl oxyacetate chlorhydrate.

FIGURE 1 indicates the influence Iof the substance upon the cornary iiow an-d FIGURE 2 the inlluence upon the blood pressure. The data forming basis of the diagram represent the mean value of the results of measurement ascertained in tests on 8 animals each. |The administration of doses higher than 0.8 mg. /k-g. papaverine is im possible because otherwise a too sharp decrease in blood pressure occurs. The figures show the clear superiority of the hydroxy-coumarin derivative under our invention over the standard substance papaverine which, on the one hand lies in the degree of the iniuence upon the coronary ow and on the other hand, in the duration of this influence (see FIGURE 1) and, furthermore, they show the difference in the `change of blood pressure (see FIGURE 2).

On the same test conditions some further substances of our invention had pharmacologically been tested and the mean values of the test results obtained are indicated in the following table.

l coronary administration of the following substances and papaverine in equal dosages.

-I-ihaving the same action as papaverine and -I- +:hav1ng an action intenser and longer vthan papaverine.

For clinical investigation there has been used especially the 3--diethylaminoethyl-4-methylcoumarin-7-ethyl oxyacetate chlorhydrate. In various clinics the preparation was administered both in the'form of'drages and in the form of solutions for intravenous and intramuscular injection in the case of most diversified clinical appearances. The drages were administered in a dosage of 15-50 milligrams three times daily and the intravenous solution was given in a dosage of 10-20 milligrams once daily. In none of the cases, side-eiects of the substance had been observed. The following diagnoses had been made in the patients singled out for these tests: hypercholesterinemia, coronary sclerosis, myocardial infarction, stenocardia, cardiosclerosis, coronary insufficiency and angina pectoris gravis. In practically all of the cases under examination a signicant improvement in the state of health of the patients was observed, which led to a complete redress of their pains and complaints.

In the preparation of drages and tablets containing as active ingredient the 7-hydroXy-coumarin derivatives of our invention, these substances may be admixed with solid tabletting adjuvants, such as starch, lactose, talc andthe like. Any of the tabletting materials used in pharmaceutical practice may be employed. For the preparation of the injection solutions there are particularly suited the derivatives of the 7-hydroxy-coumarins being basically substituted since they are water-soluble in the form of their salts. Injection solutions of water-insoluble products may of course be prepared in the conventional manner by concurrently using well-known suspending agents, emulsiers and/ or solubilizers.

The following examples are given for the purpose of Maximum Duration Change Substance LD g./kg. Dosage increase in of action in blood mouse, i.v. mgJkg. i.v. the coronary in minutes pressure,

110W, percent percent Papaverine 0. O33 0. 8 24 S -20 S--diethylaminoethyl-4-methylcoumarin-7-ethyl oxyacctate chlor- 0.8 22 60 +2 hydrate 0. O34 1. 265 35 v 60 +2 2.0 67 75 -4 3-pyrrolidinoethyl-4-methyl-coumarln 7-ethyl oxyacetate chlorhydrate 0. 04 1.0 53 26 i0 3--piperidinoethyl-t-methyl-conrnarin- 0.2 Y 26 19 +2. 2 7-ethy1 oxyacetate chlorhydrate 0.016 0. 4 37 28 -0. 5

1.0 7.4 50 :1:0 3-/3-morpholino-ethy1-4-methy-coumarin-7-cthyl oxyacetate chlorhydrate. 0. 1l 1. 0 21 16 i0 3--piperidinoethyl-4-methyl7allyloxy coumarin chlorhydrate 0. 048 1. 0 94 3() +11. 3 3-/S-diethylaminoethyl4-phenyl-coumarin-7-ethyl oxyacetate chlorhydrate. 0.02 1.0 88 40 (l) 3[l.3bis(diethy1amino)-isopropy1]4- methyl-conmarin-7-ethyl-oxyacetate chlorhydrate 0. 058 0. 8 43 65 3-B-diethylaminoethyl4-methylcou marin-7-oxyacetic acid aminoethy1 amide 2- 0 130 40 115% until 10 minutes after the injection, later i-O%.

l-:having the same action as papaverne and Y -l- -l- :having yan action intenser and longer than papaverme.

Furthermore, comparative tests had been made on the characterizing the substances of the present invention.

same conditions as described before, however, with intra- All temperatures given are in degrees centigrade.

EXAMPLE 1 14.3 grams 4-phenyl-7-hydroxy-coumarin (prepared according to the method specified in Org. Synth. vol. 2l, page 23 by condensation of benzoylacetic acid ethyl ester with resorcin in .concentrated sulfuric acid) are dissolved in 150 ccm. methylethyl ketone and admixed with 10 grams anhydrous potassium carbonate. This mixture is stirred for one hour at 70 and then 13 grams bromoacetic acid ethyl ester and 0.5 gram potassium iodide are added. It is heated until boiling and stirred for 8 hours at the boil. The reaction mixture is filtered oi Starting materials Final product Melting Yield, point percent 3-phenyl-4-methyl-7-hydrox- Chloroacetic acid-isopropyl aphenyl-i-methyl-coumar- 13S-140 70 yacoumarm. ester. in-7-isopropyl oxyacetate. 3-ethylA-phenyl-7-hydroxy- Chloroacetic acid-tert-buty1 3-ethyl-4-phenyl-coumarin- 122-123 64 coumarin. ester. 7-tert.butyl oxyacetate.

Do Chloroacetic acid-isopropyl -ethylA-phenytcoumarin- 124125 77 ester. 7is0propyl oxyacetate. 3-benzyl4methyl7hydrox Bromacetic acid-ethyl ester 3-benzy1-4methyl-couma 117-120 66 y-coumarln.

with suction in the heat and the filtratey is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride, washed several times with diluted sodium hydroxide solution and the solution of methylene chloride is evaporated to dryness. The raw product may be recrystallized from ethyl acetate for further purification. White needles having a melting point of l37-138 are obtained.

Yield: 14 grams 4-phenyl-coumarin-7-ethyl oxyacetate (=71.8% of the theory).

EXAMPLE 2 18 grams 3-butyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of a-butylacetic acid ethyl ester with resorcin according to the method specied in Org. Synth. vol. 21, page 23) are suspended in 200 ccm. methylethyl ketone. 12 grams anhydrous potassium carbonate are added and the mixture is stirred for l hour at 70. Then 0.5 gram potassium iodide are introduced into the reaction mixture and 16 grams bromoacetic acid ethyl ester are allowed to drop in. The mixture is heated until boiling and stirred for 8 hours at the boil. Then the reaction mixture is filtered ofrr with suction in the heat and worked up as indicated in Example 1. The raw product may be recrystallized from ethyl acetate for further purication. The 3-butyl-4-methyl-coumarin-7- ethyl oxyacetate thus obtained forms white needles having a melting point of 78.

Yield: 20 grams=83.5% ofthe theory.

EXAMPLE 3 17.6 grams 4-methyl-7-hydroXy-coumarin (prepared by the method indicated in Org. Synth. vol. 21, page 23) are dissolved in 180 ccm. methylethyl ketone and, whilst adding 16 grams anhydrous potassium carbonate, they are allowed to react with 18.5 grams bromoacetic acid ethyl ester according to Example 1. Thus, 4-methyl- 1coumarin7ethyl-oxyacetate having a melting point of 98-l00 are obtained.

Yield: 19 grams=72.5% of the theory.

EXAMPLE 4 20 grams 3-phenyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of resorcin with a-phenyl-acetoacetic acid ethyl ester as indicated in J. Chem. Soc. 109, 110 and I. Chem. Soc. 127, 1983) are suspended in 200 ccm. methylethyl ketone and admixed with 20 grams anhydrous potassium carbonate. The mixture is stirred for one hour at 70 and then 15 grams chloroacetic acid tert. butyl ester are allowed to drop in. Subsequently, it is heated until boiling and stirred for another 9 hours at the boil. Now the reaction mixture is filtered olf with suc- EXAMPLE 5 12 grams 3-allyl-4-methyl-7-hydroxy-coumarin are dissolved in ccm. methylethyl ketone and admixed with 12 grams anhydrous potassium carbonate. This mixture is stirred for 1 hour at 70 and then 11 grams bromoacetic acid ethyl ester are allowed to drop in. Then the mixture is stirred under reflux for another 9 hours. According to the recipe indicated in Example l, 3-allyl-4- methyl-coumarin-7-ethyl oxyacetate having a melting point of 42-44 is obtained in a good yield.

EXAMPLE 6 18.7 grams 3--diethylaminoethyl-4-methyl-7-hydroxycoumarin chlorhydrate are dissolved in 200 ccm. methylethyl ketone and 18 grams anhydrous potassium carbonate are added. The mixture is stirred for l hour at 70 and then 12 grams bromoacetic acid ethyl ester are allowed to drop in. The reaction mixture is stirred under reflux for 9 hours and then it is ltered off with suction in the heat. The filtrate is concentrated in the vacuum to Adryness and the resultant residue is dissolved in ether. The etheric solution is washed with `diluted caustic soda solution for several times and, subsequently, dried with Glaubers salt. By introduction of hydrochloric acid gas into the etheric solution the reaction product is precipitated in the form of chlorhydrate.

Yield: 15 grams 3--diethylaminoethyl-4-methylecoumarin-7-ethyl oxyacetate chlorhydrate having a melting point of 154-156 (equal 63% of the theory).

According to the process described in this example there may be prepared in an analogous manner the following :compounds of the general formula I /Ri R Melting R1 R2 R3 point of the chlorhydrates -diethylaminoethyl Methyl Ethyl 220-222 D0 d0 Allyl 198201 Do do Butyl 288-290 -piperidinoethyl do Allyl 220-222 -diethylarninoethyl Phenyl- Ethyl 15S-160 oxyacete.

piperidinoethyl Methyl do 208209 -morpholinoeth l do do 20f1f205 -pyrrolidinoethyl do do R32-183 'y-dimethylaminopropyl do do 18o-182 1,3bis(diethylamino)-isopropyl do do 176 The 3 diethylaminoethyl 4 methyl coumarin- 7ethy1 oxyacetate chlorhydrate described in this example can be saponiiied to the free acid in a known method by dissolving 4 grams of the chlorhydrate in 40 ccm. water and heating this solutionfor 4 hours under reflux. When subsequently concentrating the aqueous solution in the vacuum to dryness, a white crystalline residue is obtained which represents the 3--diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid chlorhydrate having a melting point of 70-75. The yield of the saponification is quantitative. l

EXAMPLE 7 14 grams 3carbethoxyrnethyl-4-methyl-5,7-dihydroxycoumarin (prepared by condensation of phloroglucine with acetylsuccinic acid diethyl ester according to the method indicated in Chemical Abstracts vol. 37, 14302 (1943) are suspended in 200 ccm. methylethyl ketone and 20 grams anhydrous potassium carbonate are added. This mixture is stirred for 1 hour at 70 and then 20 grams -bromoacetic acid ethyl -ester are allowed to drop in.

Then the mixture is heated until boiling and stirred for 9 hours at the boil. The reaction mixture is ltered off with suction in the heat and the filtrate is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride and washed for several times with diluted caustic soda lye. After drying, the methylene chloride layer is concentrated in the vacuum to dryness and the residual raw product is puried by recrystallization from a mixture of ethyl acetate/benzine (1:1).

Yield: 13 grams 3-carbethoxymethy1-4-methyl-coumarin-5.7-di-(ethyl oxyacetate) having a melting point of 110-1^12 (=57.5% ofthe theory).

EXAMPLE 8 grams 3--diethylaminoethyl-4-methyl-coumarin-7- ethyl oxyacetate chlohydrate are stirred together with 75 grams ethylene diamine for about 15 hours at 20-25". The resultant colorless precipitate is iiltered off with suction, washed with water and dried. Thus, 8 grams 3-- diethylarninoethyl-4-methyl-coumarin-7-oxyacetic acid aminoethylamide are obtained which, after recrystallization from Water, are colorless crystals having a melting point of 1184119".

When using concentrated ammonia instead of ethylene diamine, there is obtained in an analogous manner the 3--diethylarninoethyl-4-methyl-coumarin-7-oxyacetic acid amide in the form of colorless crystals having a melting point of 1186-187".

When using in this example instead of ethylene diamine, one of the following amines, the corresponding amides of the 3--diethylaminoethyl-4-methyl-coumafin- 7-oxyacetic acid are obtained;

.Amine used Final product Melting point Asymmetric di- 3-18-diethylaminocthyl-i-methyl- 122-124" ethyl-ethylene coumarin-7-oxyacetic acid dietl1- diamine. ylarninoethylamide. Hexamethylene B--diethylaminoethyl-4-methyl-cou- 194 diamino. marin-7-oxyacetie acid maminohexylarnde. y-dimethyl-amino- 3-pS-diethylarninoethyl-4-methyl-cou- 120 propylarnine. marin-7-oxyacetic acid'ydimethyl aminopropylamide. Butylamine 3--diethylaminoethyl-Li-methyl-cou- 129 marin-7-oxyacetic acid butylamide. a-arnino-pyridine 3--diethylaminoetl1yl-4-1nethyl-con- 1GO-16D*2 marnJ-oxyacetic acid apyridyl ami e;

EXAMPLE 9' "ylethyl ketone is allowed to drop into the reaction mixture and is stirred for 8 hours at 70.

After cooling, the solution is ltered oi with suction and the filtrate is concentrated in the vacuum to dryness; the residue is dissolved in ethyl acetate and washed for several times with diluted sodium hydroxide solution. The ethyl acetate layer is eliminate-d and dried. Hydrochloric acid gas is introduced into this solution for precipitating the chlorhydrate of the final product. Thus, 3-,8-diethylaminoethyl 4 methyl-courmarin-7-oxyacetic acide dimethylamide chlorhydrate is obtained having a melting point of 203-206".

Yield: 14 grams=59% 0f the theory.

In an analogous manner, there is obtained the B--diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid dibutylamide chlorhydrate having a melting point of 129d 130 -by allowing 3--diethylaminoethyl-4-methyl-7-hydroxy-coumarin-chlorhydrate to react with N,N-dibutylchloroacetamide.

It will be understood that this invention is susceptible to further modication and, accordingly, it is desired to comprehend such modifications within this invention as may fall within the scope of the appended claim.

Weclaim:

3-carbethoxymethyl 4 methyl-coumarin-5.7di(ethyl oxyacetate) having the formula -CHz-COOCzHs References Cited lby the Examiner UNITED STATES PATENTS r2,680,746 6/1964 Schappi 260-343.2

, WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

JAMES A.. PATTEN,Assistant Examiner. 

